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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/61—Halogen atoms or nitro radicals
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  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
  • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
  • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
  • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention provides a novel pyridazine derivative which has an excellent interleukin-1 / S production inhibitory activity and is useful for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases, and the like.
• Related to medicine. Background art
• interleukin-11 is regulated by the interleukin-11 receptor, soluble inleukin-leukin-11 receptor, and inlein-1-lipekin-1 receptor antagonist.
• Proliferation inhibitors synthesized in such studies include compounds that inhibit the process of transmitting inflammatory signals to the cell nucleus and the transcription / translation stage, and compounds that inhibit the enzyme ICE that processes the precursor of interleukin-1. being classified.
• Compounds presumed to have the former effect include SB203580 (Tokuheihei 7-503017), FR1 67653 (Eur. J. Pharm., 327, 1997, 169-175.), ⁇ -5090 ( ⁇ 376288). ), CGP47969A (Gas troenterolgy, 1995, 109, 812-818.), A hydroxyindole derivative (Eur.
• an object of the present invention is to provide a compound having an excellent interleukin-1 / S production inhibitory action and a medicament containing the compound as an active ingredient. Disclosure of the invention
• the present invention provides a compound represented by the general formula (1):
• R 1 represents an aryl group which may have a substituent
• R 2 represents at least
• R 3 is a hydrogen atom A lower alkoxyl group, a ⁇ -genated lower alkyl group, a lower cycloalkyl group, an aryl group optionally having a substituent, an aryloxy group optionally having a substituent, A nitrogen-containing heterocyclic residue, an aminocarbonyl group which may have a substituent or a lower alkylcarbonyl group, and A is a single bond or a linear or branched lower alkylene group or a lower alkylene group;
• X represents an oxygen atom or a sulfur atom, and a dashed line represents that the inter-carbon bond at the 4-position and the 5-position is a single bond or a double bond.
• R s is a halogenated lower alkyl group
• A is a single bond.
• R 1 and R 2 are 4-methoxy Phenyl group
• X is an oxygen atom
• 4-position and carbon-carbon bond is a double bond between the 5-position
• A is a single bond, except when R s is a hydrogen atom or a 2-black port Echiru group)
• the present invention provides a drug containing the pyridazine derivative (1) or a salt thereof as an active ingredient.
• the present invention also provides use of the pyridazine derivative (1) or a salt thereof as a medicament.
• the present invention provides a method for treating a disease caused by enhanced interleukin-11 / S production, which comprises administering the pyridazine derivative (1) or a salt thereof.
• the pyridazine derivative (1) or a salt thereof has an extremely potent inhibitory effect on interleukin-1 / 3 production, and the known 5,6-diphenyl ruviridazine derivative (EUR. J. MED CHEM.. 1979, 14, 53-60).
• the pyridazine derivative of the present invention is represented by the general formula (1).
• examples of the aryl group represented by R 1 include a phenyl group, a naphthyl group, a pyridyl group and the like, and a phenyl group and a pyridyl group are particularly preferable.
• These aryl groups may have 1 to 3 substituents, such as a halogen atom, a lower alkyl group, a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group, and a lower alkyl group.
• the lower alkylsulfonyl group has 1 to 6 carbon atoms and includes, for example, a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.
• the lower alkoxycarbonyl group has an alkoxy group having 1 to 6 carbon atoms and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group and a propoxycarbonyl group.
• the lower alkylamino group has one or two alkyl groups having 1 to 6 carbon atoms, and examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, and a propylamino group.
• the lower alkyl part of these substituents may be any of linear, branched or cyclic.
• R 2 is substituted with a lower alkoxyl group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group at the 4-position, and a halogen atom, a lower alkoxyl group, a lower alkylthio group, a lower alkyls group at another position.
• a phenyl group which may be substituted by one or two members selected from a rufinyl group and a lower alkylsulfonyl group is preferable.
• halogen atom lower alkoxyl group, lower alkylthio group, lower alkylsulfinyl group, and lower alkylsulfonyl group as the substituent on the phenyl group of R 2 include the same as those described above for R 1 . It is preferred that these substituents are present only at the 4-position, 3- and 4-positions, or 3-, 4- and 5-positions.
• R 3 a lower alkoxyl group, which may have a substituent
• the same groups as those described above for R 1 can be mentioned.
• halogenated lower alkyl group examples include those in which a halogen atom is substituted for the lower alkyl group as in the case of R 1 .
• the lower cycloalkyl group has 3 to 8 carbon atoms and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
• nitrogen-containing heterocyclic residue examples include a saturated nitrogen-containing heterocyclic residue such as a piperidino group, a piperidyl group, a piperazino group and a morpholino group, and a nitrogen-containing aromatic heterocyclic residue such as a pyridyl group. It may have the same substituent as in the case of R 1 . They may be further bonded to a carbonyl group.
• the aminocarbonyl group may have the same substituents as in the case of R 1 and an aralkyl group such as a benzyl group and a phenethyl group.
• the lower alkylcarbonyl group has 1 to 6 carbon atoms, and examples thereof include a methylcarbonyl group and an ethylcarbonyl group.
• R 3 is hydrogen atom; lower alkoxyl group; halogenated lower alkyl group; lower cycloalkyl group; halogen atom, lower alkyl group, lower alkoxyl group, carboxyl group, lower alkoxycarbonyl group, nitro group, amino group, lower alkyl group A substituted or unsubstituted phenyl group, a pyridyl group or a phenyloxy group, which may be substituted with 1 to 3 selected from a quilamino group and a lower alkylthio group; a piperidino group, a piperidyl group, a piperazino group or a morpholino group which may have a substituent; A diaminocarbonyl group which may have a substituent; or a lower alkylcarbonyl group.
• the lower alkylene group is a straight or branched one having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene group, and a trimethylene group.
• the lower alkenylene group is a straight or branched one having 2 to 9 carbon atoms, preferably one having 2 to 6 carbon atoms and having 1 to 3 double bonds. Examples include a len group, a propenylene group, a butenylene group, and a butagenylene group.
• A is preferably a linear or branched lower alkylene group having 1 to 6 carbon atoms or a linear or branched lower alkenylene group having 2 to 9 carbon atoms.
• R 1 is a phenyl group or a pyridyl group in which 1 to 3 groups selected from a halogen atom and a lower alkoxy group are optionally substituted:
• R 2 is a lower alkoxyl group at the 4-position A lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group, and a halogen atom or a lower
• R 3 is a hydrogen atom; a lower alkoxyl group; Lower alkyl group; lower cycloalkyl group; 1-3 atoms selected from halogen atom, lower alkyl group, lower alkoxyl group, carboxyl group, lower alkoxycarbonyl group, nitro group, amino group, lower alkylamino group and lower alkylthio group.
• R 4 represents a linear or branched lower alkyl group or lower alkenylene group, lower cycloalkyl group or lower cycloalkylmethyl group, and X represents an oxygen atom or a sulfur atom.
• the lower alkenyl group is a linear or branched lower alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and having 1 to 2 double bonds, such as an ethynyl group, a propenyl group, and a butenyl.
• R 4 is particularly preferably an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylmethyl group.
• pyridazine derivative (1) examples include 5, 6-bis (4-methoxyphenyl) 1-2-ethyl-2H-pyridazine-13-one, and 5,6-bis (4-methoxyphenyl).
• the compound of the present invention may also exist in the form of a solvate represented by a hydrate, i.e., a tautomer of keto-enol, and such solvates and isomers are also encompassed in the present invention. You.
• the pyridazine derivative (1) of the present invention can be produced, for example, by the following method.
• R 5 represents a lower alkyl group, and R 1 , R 2 , R 3 and A have the same meaning as described above.
• 4,5-dihydro 2 H-pyridazin-3-one derivative (la; in general formula (1), A is a single bond, R 3 is a hydrogen atom, X is an oxygen atom, and the 4th and 5th positions Is a single bond)
• the 2-arylacetophenone derivative (2) is reacted with a haloacetate to give a compound (3), which is then reacted with hydrazine hydrate to give 4,5-dihydro 2H-pyridazine.
• 3- 3-one derivative (la) can be obtained.
• the 2-arylacetophenone derivative (2) as a raw material can be produced, for example, by a known method (Pharmaceutical Journal, 74, 495-497 (1954)).
• the reaction between compound (2) and the haloacetic acid ester can be carried out in a solvent in the presence of a base.
• a base examples include potassium tert-butoxide, lithium diisopropylamide (LDA), and the like, and examples of the solvent include tetrahydrofuran.
• the reaction is completed at 120 to 40 ° C. for 1 to 10 hours, preferably at 15 to 25 for 2 to 5 hours.
• the reaction between the obtained compound (3) and hydrazine hydrate can be carried out in a solvent, and may be anhydrous hydrazine in addition to hydrazine hydrate.
• a solvent lower alcohols such as ethanol, methanol, n-propanol and iso-propanol; tetrahydrofuran, 1,4-dioxane and the like can be used.
• the reaction is completed at 50 to 150 ° C for 5 to 50 hours, preferably at 80 to 100 ° C for 10 to 30 hours.
• Examples of the solvent used here include methanol, ethanol, n-propanol, isopropanol, dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like. Hydrous lower alcohols are preferred.
• the reaction is completed in 40 to 15 hours (1 to 80 hours in TC, preferably in 50 to 120 hours in 5 to 50 hours).
• the dehydrogenating agent bromine, 2,3-dichloro-5,6-dicyanone or 4-benzoquinone (DDQ) can be used. Acetic acid and the like can be used as the solvent.
• the reaction is completed at 30 to 150 ° C. for 5 to 50 hours, preferably at 50 to 120 ° C. for 10 to 30 hours.
• Glyoxalic acid produced by reacting tartaric acid with sodium periodate under acidic conditions under basic conditions is reacted with the 2-arylacetophenone derivative (2) under basic conditions to give 2-hydroquinone.
• the acid derivative (4) is obtained, it is reacted with hydrazine hydrate in a lower alcohol solvent to give a 4,5-dihydroxy 4-hydroxy-2H-pyridazin-3-one derivative (5), which is subjected to a dehydration reaction in a solvent using paratoluenesulfonic acid hydrate as a catalyst, whereby a 2 H-pyridazine-3-one derivative (lb) can be obtained.
• the reaction is carried out in a synthesis process of glyoxalic acid, The reaction is completed by reacting at 30 at 20 to 180 minutes, preferably at 0 to 25 minutes at around 30 to 60 minutes.
• the reaction with the compound (2) is preferably carried out at 0 to 120 ° C, preferably at room temperature for 10 to 25 hours, and then at 70 ° C for 0.5 to 2 hours. finish.
• As the solvent lower alcohols such as ethanol, methanol, n-propanol and iso-propanol tetrahydrofuran, and 1,4-dioxane can be used.
• the reaction of the compound (4) with hydrazine hydrate can be performed using anhydrous hydrazine in addition to hydrazine hydrate.
• the reaction is carried out at 50 to 150 for 5 to 30 hours, preferably at 80 to 1 hour. It ends in 10 to 20 hours at 00 ° C.
• the solvent lower alcohols such as ethanol, methanol, n-propanol and iso-propanol; tetrahydrofuran, 1,4-dioxane and the like can be used.
• para-toluenesulfonic acid hydrate or the like can be used as a catalyst.
• toluene, benzene and the like can be used as the solvent.
• the reaction is completed at 50 to 150 ° C. for 3 to 50 hours, preferably 80 to 13 (TC for 5 to 30 hours).
• R 3 and A have the same meaning as described above, and Y represents a halogen atom or a reactive esterified OH group.
• Examples of the base used in the reaction include inorganic bases such as potassium carbonate and sodium carbonate; and organic bases such as metal alkoxide. N, N-dimension Tilformamide, dimethyl sulfoxide, acetone, methylethyl ketone, etc. can be used.
• the reaction is completed at 20 to 150 ° C for 1 to 20 hours, preferably at 50 to 130 ° C for 2 to 10 hours.
• the compound (1c) in which the 2-position is a piperidylalkyl group is a compound in which the nitrogen atom of the starting material piperidylalkanol is protected and then the hydroxyl group is converted to a reactive ester, and the compound (lb) After the reaction, the product can be produced by deprotection. Further, by subjecting this to N-lower alkylation, an N-lower alkylpyridylalkyl derivative can be produced.
• a tert-butoxycarbonyl group, benzyloxycarbonyl group, dimethylphosphinothioyl group and the like are preferable, and the compound protected by these groups is a piperidyl alkanol. It can be obtained by reacting di-tert-butyl carbonate, benzyloquine carbonyl chloride or the like in the presence of a base such as triethylamine or 4-dimethylaminopyridine.
• tetrahydrofuran tetrahydrofuran
• getyl ether ethyl acetate
• methylene chloride chloroform
• N, N-dimethylformamide dimethyl sulfoxide
• ethanol ISO-propanol and the like
• the reaction is completed in 15 to 50 hours at 5 to 50 hours, preferably at 0 to 20 hours in 1 to 30 hours.
• a tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group, and the like are preferable.
• Compounds having these groups include N-protected piberidyl alkanol, pyridine, triethylamine, collidine and the like. In the presence of a base. It can be obtained by reacting toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride and the like.
• pyridine tetrahydrofuran, methyl ether, ethyl acetate, methylene chloride, chloroform, N, N-dimethylformamide, dimethylsulfoxide and the like can be used. Reaction to 1-15 —
• the reaction of compound (1b) with a reactive ester derivative of N-protected piberidyl alkanol can be performed in a solvent in the presence of a base.
• a base examples include inorganic bases such as carbonated sodium carbonate and sodium carbonate; and organic bases such as metal alkoxide.
• the solvent N, N-dimethylformamide, dimethylsulfoxide, acetone, methylethylketone, and the like can be used.
• the reaction is completed at 20 to 150 ° C for 1 to 30 hours, preferably at 50 to 130 ° C for 2 to 10 hours.
• Deprotection of the protecting group on the nitrogen atom of the piperidyl group can be carried out by heating in a solvent in the presence of an acid catalyst.
• the acid used here include hydrochloric acid, sulfuric acid, and acetic acid, and these acids may be diluted with water. Preferred is 2 to 1 N hydrochloric acid, and particularly preferred is 4 to 8 N hydrochloric acid.
• As the solvent tetrahydrofuran, methanol, ethanol, isopropanol, N, N-dimethylformamide and the like can be used. The reaction is completed in 0.5 to 10 hours at 40 to 150 ° C, preferably in 2 to 5 hours at 50 to 130.
• the compound (1c) in which the 2-position is a piperidinoalkyl, piperazinoalkyl or morpholinoalkyl group is a 2-position obtained by reacting the compound (1b) with an alkylene chlorohydrin or an alkylene carbonate.
• the hydroxyalkyl The compound can be produced by deriving a hydroxyl group of a body into a reactive ester and then reacting the corresponding amine.
• the quaternary ammonium salts used herein include tetraethylammonium iodide, tetraethylammonium bromide, tetra-n-butylammonium iodide, and tetra-n-butylammonium bromide. And the like.
• the solvent include N, N dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and the like.
• the reaction is completed at 80 to 180 ° C for 0.5 to 10 hours, preferably at 120 to 160 ° C for 1 to 5 hours.
• the reactive ester group of the hydroxyl group is preferably a tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group, and the like.
• Compounds having these groups may be added to a hydroxyalkyl compound in the form of a base such as pyridine, triethylamine, or collidine. In the presence of, no ,. It can be obtained by reacting toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, benzenesulfonyl chloride and the like.
• pyridine tetrahydrofuran
• getyl ether ethyl acetate
• methylene chloride chloroform
• N, N-dimethylformamide dimethylsulfoxide and the like
• the reaction is completed in 15 to 50 hours at 1 to 50 hours, preferably at 5 to 30 ° C for 1 to 10 hours.
• reaction between the reactive ester derivative and the amine can be performed by heating the reactive ester derivative in a solvent or in the absence of a solvent in the presence of an excess of amine, or by using pyridine, triethylamine, 1,8 diazavisic ⁇ [5. 4.0]
• Ende force—reaction can be carried out by reacting an amine in the presence of an organic amine such as 7-diene (DBU) or an inorganic base such as lithium carbonate or sodium carbonate.
• DBU 7-diene
• the solvent N, N-dimethyl
• dimethyl sulfoxide, pyridine, black form, methylene chloride, toluene, benzene and the like can be used.
• the reaction is completed at 0 to 150 at 1 to 10 hours, preferably at 50 to 130 at 1 to 5 hours.
• the hydrolysis of the ester group can be carried out by subjecting the ester compound to a conventional method in the presence of a base such as caustic soda and caustic potash.
• Examples of the reactive derivative of the carboxylic acid include an acid halide, a mixed acid anhydride and the like.
• the acid halide can be produced by oxalyl chloride, thionyl chloride, thionyl bromide, etc., and the mixed acid anhydride is an anhydride.
• the reaction between these reactive ester derivatives and amines is carried out by reacting the reactive ester derivative with an excess of amine in a solvent or without solvent, or by using an organic amine such as pyridine, triethylamine or DBU; Presence of inorganic bases such as carbonated lime and sodium carbonate
• the reaction can be carried out by reacting an amine in the presence.
• As the solvent tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, pyridin, chloroform, methylene chloride, toluene, benzene and the like can be used.
• the reaction is completed at 0 to 150 at 1 to 10 hours, preferably at 50 to 130 at 1 to 5 hours.
• the derivative in which R 3 is an aminophenyl group is obtained by reducing the nitro group of the compound in which R 3 is a nitrophenyl group in the compound (1c). Further, by N-lower alkylation of the compound, an N-lower alkylaminoamino compound can be produced.
• the nitro group can be reduced by hydrogenation in an inert solvent such as ethyl acetate or ethanol using palladium-one carbon or Raney-nickel as a catalyst.
• an inert solvent such as ethyl acetate or ethanol using palladium-one carbon or Raney-nickel as a catalyst.
• Examples of the base used in the N-lower alkylation reaction include sodium hydrogen carbonate, potassium carbonate, pyridine, and triethylamine.
• As the solvent acetone, dimethyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran, a mixed solvent of these solvents and the like are preferable.
• the reaction is completed at 20 to 150 ° C for 0.5 to 10 hours, preferably at 50 to 130 ° C for 1 to 5 hours.
• Compound (1c) can be produced in the same manner as when producing compound (lb) from compound (la) using compound (Id) as a raw material.
• the selective oxidation reaction can be performed using meta-chloroperbenzoic acid, aqueous hydrogen peroxide, or the like as an oxidizing agent.
• the reaction is preferably performed at 130 to 30 ° C for 10_min to 10 hours, preferably. It takes 30 minutes to 1 hour at 110 ⁇ 10 ° C.
• As the solvent methylene chloride, chloroform and the like can be used.
• derivatives R 1 or R 2 is lower alkyl sulfonyl off We sulfonyl group, among the compounds (1 c), the derivative R 1 or R 2 is lower alkyl thio phenylene le radical It can be produced by oxidation.
• the 2H-pyridazin-3-one derivative is treated with Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,1,3-dithia-1,2,4-diphosphethane-1,2,4-disulfide) in a solvent in a solvent.
• Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,1,3-dithia-1,2,4-diphosphethane-1,2,4-disulfide
• the Lawesson's reagent used is preferably 0.5 to 3 equivalents, particularly preferably 1 to 5 equivalents, based on the 2 H-pyridazine-3-one derivative.
• the reaction is completed in 30 to 150 ° (at 1 to 10 hours, preferably at 50 to 100 ° and 2 to 8 hours.
• Examples of the solvent used include toluene and xylene.
• the intermediate and the target compound obtained in each of the above reactions are subjected to purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. It can be isolated and purified.
• the intermediate can be subjected to the next reaction without particular purification. It may also be obtained as a solvate of a solvent such as a reaction solvent or a recrystallization solvent, particularly as a hydrate.
• the dosage of the medicament of the present invention varies depending on age, body weight, symptoms, administration form, number of administrations, and the like, but is usually 0.01 to 100 mg / day, preferably 0 to 100 mg / day for an adult. It is preferable to administer 1 to 100 mg orally or parenterally in one or several divided doses.
• the extract was washed with saturated saline, dried over anhydrous sodium sulfate, combined with the aqueous layer, extracted with chloroform (202 ⁇ 3), and the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate.
• the solvent was distilled off from the ethyl acetate extract and the chloroform extract, and the residue obtained was distilled off.
• the product was separated and purified by Kagel column chromatography (silica gel: 50 g, chromatoform / methanol (50/1)). The eluate was evaporated to dryness under reduced pressure, and the resulting crystals were heated with ethanol. After cooling, ether was added and the mixture was allowed to stand at room temperature, and the precipitated crystals were collected by filtration and dried under reduced pressure at 6 (TC to give 7.84 g (52.43 ⁇ 40) of the title compound as pale orange crystals.
• TC chromatoform
• lithium diisopropylamide (2.0 2. solution) 2 (50.0 millimol) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes.
• methyl bromoacetate 6. (63.4 mmol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling and for 2 hours at room temperature.
• the reaction solution was diluted with toluene, washed successively with 2 ⁇ hydrochloric acid, water and saturated saline, and dried over anhydrous sodium sulfate.
• the title compound was obtained in a yield of 57.0% by treating in the same manner as in Production Example 7 using 3-monofluoro-4-methoxyphenyldiacid and Ryoji tool as raw materials.
• IR (KBr) cm- 1 1665, 1609, 1513, 1246, 965, 837, 700.
• Ii filn cm— 1 1660, 1609, 1515, 1250, 1028, 834.
• IR (film) cirr 1652, 1608, 1515, 1295, 1247, 1177, 1031, 833, 750,
• IRCKBr cm 1 1660, 1609, 1513, 1295, 1250, 1176, 1027, 838, 753.
• IR (iilm) cm— ] 1652, 1608, 1514, 1297, 1248, 1177, 1031, 834, 754.
• IRCfilm IRCfilm ⁇ -': 1661, 1609, 1514, 1297, 1247, 1179, 1034, 833, 754.
• IRCfilm ⁇ " 1 : 1652, 1610, 1514, 1296, 1251, 1180, 1034, 834, 756.
• Example 12 The same procedure as in Example 12 was carried out using 5,6-bis (4-methoxyphenyl) -12H-pyridazin-3-one as a raw material to give the title compound in a yield of 30.4%.
• IR (KBr) cm- 1 1665, 1609, 1515, 1294, 1247, 1184, 1177, 1027, 839.
• IR (KBr) cm— 1 1660, 1610, 1516, 1293, 1286, 1251, 1241, 1134, 1030,
• IR (KBr) cm— ' 1660, 1609, 1509, 1296, 1249, 1178, 1027, 833.
• IR (KBr) cm- 1 1664, 1608, 1513, 1290, 1254, 1182, 1027, 834, 786.
• the hydrochloride of the title compound was obtained in a conventional manner in a yield of 96.4%.
• the methanesulfonate of the title compound was obtained in a conventional manner in a yield of 86.0%.
• IR (KBr) cm- 1 1668, 1519, 1513, 1469, 1270, 1253, 1175, 1140.
• IR (KBr) cm- 1 1660. 1601, 1587, 1514, 1247, 1174, 1091, 953, 844, 789.
• the methanesulfonate of the title compound was obtained in a conventional manner in a yield of 66.8%.
• IRCKBr ⁇ -1 : 1669, 1598, 1578, 1510, 1228, 1160, 1096, 840, 680.

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